DESCRIPTION: Insulin resistance is a significant risk factor for non- insulin- dependent diabetes mellitus (NIDDM), hypertension,atherosclerosis, and cardiovascular disease. Despite its significant association with numerous health problems, the mechanisms underlying insulin resistance are not clearly understood. The long term objective of the investigators' research is to elucidate the cellular mechanisms by which insulin resistance is developed in skeletal muscle, the major tissue responsible for insulin-mediated glucose uptake. In this application the investigators propose to test the hypothesis that during the development of insulin resistance impairment of intracellular glucose metabolism in skeletal muscle precedes and causes impairment of insulin's action on glucose transport. The implication of the hypothesisis that reduced insulin action on glucose transport (or uptake) is a secondary and adaptive response of muscle to prevent accumulation of substrate when its capacity for glucose metabolism is reduced.To test this hypothesis they propose to examine whether impairment of skeletal muscle glucose metabolism (e.g., glycolysis) precedes decreases in insulin's action on glucose transport during chronic development of insulin resistance with high fat feeding in rats. In addition, they propose to examine whether acute suppression of glucose metabolism in skeletal muscle causes subsequent down regulation of insulin's action on glucose transport during prolonged hyperinsulinemic glucose clamps. The investigators also propose to investigate the hexosamine biosynthesis pathway, recently discovered to regulate insulin action in cultured fat cells, as a potential mechanism to link impaired glucose metabolism to the modulation of insulin action in skeletal muscle. Finally, if the role of the hexosamine pathway is established in skeletal muscle, they propose to examine whether feeding rats with diets containing glucosamine results in insulin resistance by increasing the flux through the hexosamine pathway, and if so, whether insulin resistance causes subsequent development of hyperglycemia and/or impaired insulin secretion. This study will provide insights into the mechanisms of development of insulin resistance in skeletal muscle, which is one of the primary events in the pathogenesis of NIDDM.